Abstract
Background: Histone lysine demethylases (KDMs) are well-recognized targets in oncology drug discovery. They function at the post-translation level controlling chromatin conformation and gene transcription. KDM1A is a flavin adenine dinucleotide-dependent amine oxidase, overexpressed in several tumor types, including acute myeloid leukemia, neuroblastoma and non-small-cell lung cancer. Among the many known monoamine oxidase inhibitors screened for KDM1A inhibition, tranylcypromine emerged as a moderately active hit, which irreversibly binds to the flavin adenine dinucleotide cofactor. Material & methods: The KDM1A inhibitors 5a–w were synthesized and tested in vitro and in vivo. The biochemical potency was determined, modulation of target in cells was demonstrated on KDM1A-dependent genes and the anti-clonogenic activity was performed in murine acute promyelocytic Leukemia (APL) blasts. An in vivo efficacy experiment was conducted using an established murine promyelocytic leukemia model. Results: We report a new series of tranylcypromine derivatives substituted on the cyclopropyl moiety, endowed with high potency in both biochemical and cellular assays. Conclusion: The most interesting derivative (5a) significantly improved survival rate after oral administration in a murine model of promyelocitic leukemia.
Financial & competing interests disclosure
This work was supported by Regione Lombardia, Fondo per la Promozione di Accordi Istituzionale, Bando di Invito di cui al Decreto n. 4779 del 14/05/2009, Progetto DiVA, BioStruct-X (FP7/2007-2013, grant agreement 283570) and Rasna Research. In vitro ADME and in vivo preliminary pharmacokinetic studies in mice have been performed at Accelera Srl, Viale Pasteur 10 - 20014 - Nerviano (Milano) – Italy. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.
No writing assistance was utilized in the production of this manuscript.
Ethical conduct of research
All animal studies were carried out in compliance with Italian Legislative Decree No. 116 dated 27 January 1992, and the European Communities Council Directive No. 86/609/EEC concerning the protection of animals used for experimental or other scientific purposes and according to Institutional Policy Regarding the Care and Use of Laboratory Animals (project-specific license number 11/2012).